Autoimmune diabetes in NOD mice is a paradigm of failed T cell tolerance to 'self' antigens. Dysregulated T cell negative selection, both at the thymic and peripheral levels, likely contributes to the accumulation of islet-reactive clones in NOD mice and T1D susceptible humans. Once these cells accumulate in the peripheral lymphoid milieu, the parameters governing the ontogeny of their differentiation into diabetogenic effectors remain poorly understood. Contrary to the popular notion that autoimmunity results from promiscuous lymphocyte activation, we recently characterized a profound deficiency in the progression of NOD T cell division upon activation. This aberrancy was not due to an intrinsic T cell defect but, rather, was imposed by a deficiency in APC mediated co-stimulation, characteristic of NOD mice. This APC aberrancy has two, paradoxically, opposing effects: 1) it limits the capacity for negative selection of autoreactive T cells allowing their retention by the immune system and 2) it tempers full activation of islet reactive T cells to a diabetogenic state, at least temporarily. Thus, the pre-diabetic NOD immune system exists in a tenuous state where autoreactive T cells stand poised and can become fully activated upon receipt of an optimal strength stimulus from the APC compartment. In the present application, we will determine the impact of changes in peripheral T cell homeostasis upon the potency of activation stimuli provided by the NOD APC compartment. Our overarching hypothesis is that the senescing thymus imposes changes in peripheral T cell homeostasis, which tip the balance in favor of diabetogenic effector T cells differentiating from their precursors in NOD mice. A detailed understanding of the parameters governing conversion of a quiescent repertoire of islet-reactive CD4 T cells to a destructive state will allow the eventual design of effective immune-intervention strategies for diabetes prevention.